Background: Inborn errors of immunity are mostly monogenic. However, disease phenotype and outcome may be modified by the coexistence of a second gene defect.
Objective: We sought to identify the genetic basis of the disease in a patient who experienced bleeding episodes, pancytopenia, hepatosplenomegaly, and recurrent pneumonia that resulted in death.
Methods: Genetic analysis was done using next-generation sequencing. Protein expression and phosphorylation were determined by immunoblotting. T-cell proliferation and F-actin levels were studied by flow cytometry.
Results: The patient harbored 2 homozygous deletions in STX11 (c.369_370del, c.374_376del; p.V124fs60∗) previously associated with familial hemophagocytic lymphohistiocytosis and a novel homozygous missense variant in SLP76 (c.767C>T; p.T256I) that resulted in an approximately 85% decrease in SLP76 levels and absent T-cell proliferation. The patient's heterozygous family members showed an approximately 50% decrease in SLP76 levels but normal immune function. SLP76-deficient J14 Jurkat cells did not express SLP76 and had decreased extracellular signal-regulated kinase signaling, basal F-actin levels, and polymerization following T-cell receptor stimulation. Reconstitution of J14 cells with T256I mutant SLP76 resulted in low protein expression and abnormal extracellular signal-regulated kinase phosphorylation and F-actin polymerization after T-cell receptor activation compared with normal expression and J14 function when wild-type SLP76 was introduced.
Conclusions: The hypomorphic mutation in SLP76 tones down the hyperinflammation due to STX11 deletion, resulting in a combined immunodeficiency that overshadows the hemophagocytic lymphohistiocytosis phenotype. To our knowledge, this study represents the first report of the opposing effects of 2 gene defects on the disease in a patient with an inborn error of immunity.
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http://dx.doi.org/10.1016/j.jaci.2023.08.005 | DOI Listing |
Cancer Treat Rev
December 2024
SOLTI Cancer Research Group, Barcelona, Spain; Statistics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Electronic address:
Introduction: Antibody-drug conjugates (ADCs) trastuzumab-deruxtecan (T-DXd) and sacituzumab-govitecan (SG) provided significant progression-free survival (PFS) and overall survival (OS) improvements over chemotherapy (CT) in pretreated hormone receptor-positive (HR+) and triple-negative (TN)/HER2-low metastatic breast cancer (MBC). However, no direct comparison between the two exists, nor with the more recent datopotamab-deruxtecan (Dato-DXd).
Methods: We conducted a network meta-analysis (NMA) to compare efficacy and safety of T-DXd and SG in CT-pretreated HR+ and TN/HER2-low MBC and assess their benefit over standard CT, exploring also a comparison with Dato-DXd.
Clin Nutr
December 2024
Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien, Taiwan. Electronic address:
Background: Trimethylamine N-oxide (TMAO) is a gut microbial metabolite derived from dietary l-carnitine and choline. High plasma TMAO levels are associated with cardiovascular disease and overall mortality, but little is known about the associations of TMAO and related metabolites with the risk of kidney function decline among patients with chronic kidney disease (CKD).
Methods: We prospectively followed 152 nondialysis patients with CKD stages 3-5 and measured plasma TMAO and related metabolites (trimethylamine [TMA], choline, carnitine, and γ-butyrobetaine) via liquid chromatography‒mass spectrometry.
Leuk Lymphoma
December 2024
Division of Hematology, Mayo Clinic, Rochester, MN, USA.
Over the past two decades, new agents for multiple myeloma (MM) have significantly improved patient outcomes, particularly for those with standard-risk disease, who now have a median overall survival of over a decade. However, this benefit is less pronounced in high-risk and ultra-high-risk MM, where median survival ranges from 3 to 5 years. The definition of HRMM continues to evolve and is driven by the genomic features, disease burden, and medical comorbidities.
View Article and Find Full Text PDFCell Rep
December 2024
Institute of Biochemistry, Christian-Albrechts-University Kiel, Olshausenstrasse 40, 24118 Kiel, Germany. Electronic address:
Genetic variants in TMEM106B, coding for a transmembrane protein of unknown function, have been identified as critical genetic modulators in various neurodegenerative diseases with a strong effect in patients with frontotemporal degeneration. The luminal domain of TMEM106B can form amyloid-like fibrils upon proteolysis. Whether this luminal domain is generated under physiological conditions and which protease(s) are involved in shedding remain unclear.
View Article and Find Full Text PDFJ Intern Med
December 2024
Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea.
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